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Stronger Inhibition (stronger + inhibition)
Selected AbstractsAN S296R MUTATION IN THE HUMAN ANDROGEN RECEPTOR CAUSES ACTIVATION OF THE RECEPTOR BY NON-ANDROGENIC STEROIDS AND STRONGER INHIBITION BY THE NUCLEAR RECEPTOR COREPRESSOR N-coRCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 10 2008Yi-Dong Li SUMMARY 1Mutation of the androgen receptor (AR) is believed to contribute to androgen-independent growth of prostate cancer. In the present study, we examined the functional changes associated with the novel somatic mutation S296R in the N-terminal domain of the AR identified from one recurrent prostate cancer sample. 2The results indicate that the S296R mutation does not differ obviously from the wild-type AR in its ability to bind the synthetic androgen methyltrienolone, or in its transcriptional activity induced by dihydrotestosterone (DHT) in the absence or presence of the overexpression of coactivators (steroid receptor coactivator-1, transcription intermediary factor-2, cAMP response element-binding protein-binding protein and p300). However, S296R was found to differ from wild-type AR in that its transcriptional activity could be activated by high concentrations (1 µmol/L) of 17,-oestradiol and progesterone and its transactivity induced by DHT was more obviously inhibited by overexpression of the nuclear receptor corepressor N-coR in CV-1 cells. 3These findings indicate that a point mutation (S296R) in the N-terminal domain of the AR can decrease the ligand specificity of the AR and alter the interaction between S296R and the corepressor N-coR. [source] Effect of Cu stress on the invertase activity and root growth in two populations of Rumex dentatus L. with different Cu toleranceENVIRONMENTAL TOXICOLOGY, Issue 4 2008Yu Huang Abstract There has been no study on key enzymes in sucrose cleavage in metallophyte plants so far, which may be crucial for the plants' root growth and heavy metal tolerance maintenance. Acid invertases are rate-limiting enzymes in sucrose metabolism. Here, we tested the hypothesis that the roots of copper-tolerant plants should manifest a higher activity of acid invertases than nontolerant plants both for supporting growth and for their maintaining tolerance under Cu stress. Two populations of Rumex dentatus L., one from an ancient waste heap at a Cu mine (Cu-tolerant population), and the other from a noncontaminated site (Cu nontolerant population), were used in the experiments. The seedlings of Rumex dentatus L. were exposed to 0, 10, and 40 ,M CuCl2 for 14 days. Cu exposure had a stronger inhibition on root growth and thus resulted in a lower root/shoot ratio in the plants of nontolerant population compared with the Cu-tolerant population. Cu exposure showed a stronger inhibition of acid invertase activity of Cu nontolerant plants than Cu tolerant plants, whereas neutral/alkaline invertase was insensitive to Cu. A positive correlation between the activity of acid invertases and the root growth and root/shoot ratio was observed. The results suggested that the higher activities in acid invertases of Cu-tolerant population might at least partly associate with the plants' Cu tolerance, and their higher activities in acid invertases in turn played an role in maintenance of the Cu tolerance by supplying carbon and energy for tolerance mechanisms. © 2008 Wiley Periodicals, Inc. Environ Toxicol, 2008. [source] Perinatal exposure to bisphenol-A changes N -methyl- D -aspartate receptor expression in the hippocampus of male rat offspringENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 1 2010Xiao-Hong Xu Abstract Bisphenol-A (BPA) is one of the most common environmental endocrine disrupters with mixed estrogen agonist/antagonist properties. The toxicity of BPA has been extensively evaluated in a variety of tests in rodents, including developmental and reproductive toxicity, and carcinogenicity. The objective of the present study is to evaluate whether or not perinatal maternal exposure to BPA at 0.05, 0.5, 5, 50, and 200 mg/kg/d affects N -methyl- D -aspartate (NMDA) receptor (NMDAR) subunits NR1, NR2A, 2B, estrogen receptor beta (ER,), and aromatase cytochrome P450 (P450arom) protein expressions of hippocampus in male rat offspring during postnatal development. Western-blotting analyses showed that perinatal exposure to BPA significantly affected the expression of NMDAR subunits. At the lower doses of 0.05 to 50 mg/kg/d, BPA concentration dependently inhibited the expression of NMDAR subunits. However, at the higher dose (200 mg/kg/d), the effects of BPA on these subunits were different, with a stronger inhibition of NR1 expression and a slighter inhibition of NR2A, 2B expression when compared with those at the lower dosage of BPA. In addition, perinatal exposure to BPA inhibited the expression of ER, protein, but increased P450arom protein expression in a concentration-dependent manner, especially during the early postnatal period (the first 1,3 postnatal weeks). No significant influence of BPA on P450arom was observed at postnatal week 8. These data suggest that environmental BPA exposure may affect the development of the brain, enhancing the local biosynthesis of estrogen in the brain, inhibiting ER, and NMDAR expressions. Environ. Toxicol. Chem. 2010;29:176,181. © 2009 SETAC [source] Poster Sessions BP06: Neurogenesis, Stem Cells and ApoptosisJOURNAL OF NEUROCHEMISTRY, Issue 2002J. Qiu The NF-,B transcription factor regulates bcl-x gene expression, which may determine hypoxia-induced neuronal apoptosis. We examined hypoxia-induced NF-,B and Bcl-xL changes in rat hippocampus. We showed differential hypoxia-induced NF-,B binding to the bcl-x promoter CS4 and IgG,,B enhancer sequences by rat hippocampal nuclear extracts. The differential NF-,B binding to these two promoter sequences was also determined in a contused spinal cord injury model and in vitro studies with LPS-treated Hela cells. There was tissue-, gene promoter-specific and time-dependent regulation of bcl-x gene expression by NF-,B in support of the hypothesis that NF-,B has tissue- and gene-specific regulatory effects and that these effects may account for both the pro- and anti-apoptotic roles assigned to NF-,B in different apoptotic processes. We applied ,decoy' oligonucleotides with sequences specific to different promoters to the rat hippocampus and measured ,decoy' inhibitory effects on nuclear NF-,B binding. The IgG-,B enhancer sequence ,decoy' showed stronger inhibition on nuclear NF-,B c-Rel/p50 binding to the bcl-x gene promoter CS4 sequence when compared to NF-,B p50/p50 binding to the same sequence. This result suggests that the ,decoy' approach has the potential to selectively manipulate NF-,B regulation of gene expression in response to hypoxia. Acknowledgements:, Supported by NINDS NS-39161, Shriner Grant 8710 and a Grant from the Sealy Center on Aging to J. Qiu. [source] Preparation and antioxidant activity of wheat gluten hydrolysates (WGHs) using ultrafiltration membranesJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 5 2008Xiangzhen Kong Abstract BACKGROUD: Many hydrolysates from animal and plant proteins have been found to possess physiological activities. Wheat gluten, an important by-product of the wheat starch industry, is produced worldwide in enormous quantities. In this study, wheat gluten hydrolysates (WGHs) were obtained by enzymatic hydrolysis and fractionated using ultrafiltration membranes. The antioxidant activities of the hydrolysates were investigated by various antioxidant assays, including the ability to inhibit the autoxidation of linoleic acid and the scavenging effect on free radicals. Amino acid composition and molecular weight distribution were also evaluated to determine their relationship with antioxidant activity. RESULTS: The pepsin hydrolysate (PeWGH) had the highest activity and was ultrafiltrated into three major types, PeWGH I (5,10 kDa), PeWGH II (3,5 kDa) and PeWGH III (<3 kDa). PeWGH III showed stronger inhibition of the autoxidation of linoleic acid and higher scavenging activity against 2,2-diphenyl-1-picrylhydrazyl, superoxide and hydroxyl free radicals. Furthermore, PeWGH III had the highest total hydrophobic amino acid content (45.11 g per 100 g protein), and its molecular weight distribution ranged from 1700 to 100 Da. CONCLUSION: The low molecular weight and amino acid composition of PeWGHs were found to be strongly correlated with their antioxidant activity. PeWGH could be used as a natural antioxidant in the pharmaceutical and food industries in the future. Copyright © 2008 Society of Chemical Industry [source] Comparative analysis of antitumor activity of CD40L, RANKL, and 4-1BBL in vivo following intratumoral administration of viral vectors or transduced dendritic cellsTHE JOURNAL OF GENE MEDICINE, Issue 2 2006Zoya R. Yurkovetsky Abstract The tumor necrosis factor (TNF) family comprises a group of ligands that regulate cell proliferation, differentiation, activation, maturation and apoptosis through interaction with the corresponding TNF receptor family members. In this study, we have evaluated whether adenovirus-mediated intratumoral gene transfer of CD40L, RANKL, or 4-1BBL elicits an immune response to established murine MC38 and TS/A tumors. Intratumoral administration of the recombinant adenoviral vectors expressing CD40L, RANKL or 4-1BBL 7 days post-tumor cell inoculation resulted in significant inhibition of MC38 tumor growth for all three ligands when compared with control groups treated with either saline or control adenovirus. However, intratumoral injection of Ad-4-1BBL or Ad-CD40L resulted in a significantly stronger inhibition of TS/A tumor progression than did Ad-RANKL treatment. We also demonstrated that intratumoral administration of dendritic cells (DC) transduced with adenoviral vectors encoding the TNF-related ligands resulted in a significant inhibition of MC38 tumor growth as compared with control groups treated with Ad-LacZ-transduced DC or saline-treated DC. In addition, DC overexpressing CD40L secreted considerably more IL-12 and expressed higher levels of the co-stimulatory molecules, CD80, CD86 and CD40, than did DC overexpressing LacZ, 4-1BBL or RANKL. We have also demonstrated that DC/CD40L, DC/4-1BBL, and DC/RANKL survived significantly longer than control DC or DC infected with the LacZ vector. Taken together, these results demonstrate that adenoviral gene transfer of CD40L, RANKL or 4-1BBL elicit a significant antitumor effect in two different tumor models, with CD40L gene transfer inducing the strongest antitumor effect. Copyright © 2005 John Wiley & Sons, Ltd. [source] Biosynthesis of New Indigoid Inhibitors of Protein Kinases Using Recombinant Cytochrome P450 2A6CHEMISTRY & BIODIVERSITY, Issue 1 2005Zhongliu-Liu Wu Glycogen synthase kinase-3 (GSK-3) is a potential drug target for a number of human diseases. Some indigoids have been found to be potent inhibitors of GSK-3, and individual compounds with better activity, specificity, and solubility are desired. In this work, a new disubstituted indigoid generation system was developed with a tryptophanase-deficient Escherichia coli strain as a host to express the human cytochrome P450 2A6 mutant L240C/N297Q, which catalyzes the oxidation of indole to isatin and indoxyl, which in turn react to generate indigoids. Forty-five substituted 1H -indoles from commercial sources were used as substrates in the system, and indigoid mixtures were tested as potential inhibitors of GSK-3. After preliminary screening, cell extracts with high inhibitory activity towards GSK-3,/, were fractionated, and the IC50 values of twelve individual indigoids were measured for GSK-3,/, as well as the protein kinases CDK1/cyclinB and CDK5/p25. Several indigoids, including an indigo, showed stronger inhibition than found in previous work. The most potent towards GSK-3,/,, dimethyl indirubin 5,5,-dicarboxylate (IC50 of 51,nM), was modified by chemical reactions. One product, indirubin 5,5,-dicarboxylic acid 5-methyl ester, inhibited GSK-3,/, with an IC50 of 14,nM and selectivity nearly 40-fold over CDK1 and CDK5. Indirubin-5-5,-dicarbonitrile was also modified to the corresponding 3,-oxime, which had low specificity but showed very high inhibition of all three kinases with IC50 values of 5, 13, and 10,nM towards GSK-3,/,, CDK1, and CDK5, respectively. Thus, this system has the potential to generate new indigoids with therapeutic potential. [source] | |||||||||||||